Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas
Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas
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DOI：
10.1038/ng0597-68
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发表时间：
1997-05-01
期刊：
影响因子：
30.8
通讯作者：
Zbar, B
中科院分区：
文献类型：
--
作者：
Schmidt, L;Duh, FM;Zbar, B
遗传性乳头状肾癌（HPRC）是最近发现的一种遗传性肾癌，其特点是易发展为多发双侧乳头状肾肿瘤（1-4）。HPRC的遗传模式与常染色体显性遗传一致，外显率降低。HPRC在组织学和遗传学上不同于遗传性肾癌的另外两种病因：von Hippel-Lindau病（VHL）和染色体易位（3;8）（5-6）。恶性乳头状肾癌的特征是染色体7、16和17三体，男性的特征是Y染色体缺失(7)。遗传性和散发性透明细胞肾癌的特征是VHL基因的两个拷贝因突变和/或高甲基化而失活（8-11）。我们发现HPRC基因位于染色体7q31.1-34上，位于D7S496和D7S1837之间的27厘米（cM）间隔。我们在HPRC家族的受影响成员的种系中发现了MET基因酪氨酸激酶结构域的错义突变，并在散发家族的一个子集：乳头状肾癌中发现了错义突变。MET基因中的三个突变位于与c-kit和RET中的密码子同源的密码子中，c-kit和RET是自然发生突变的靶原癌基因。结果表明，位于MET原癌基因的错义突变导致MET蛋白和乳头状肾癌的组成性激活。
Hereditary papillary renal carcinoma (HPRC) is a recently recognized form of inherited kidney cancer characterized by a predisposition to develop multiple, bilateral papillary renal tumours(1-4). The pattern of inheritance of HPRC is consistent with autosomal dominant transmission with reduced penetrance. HPRC is histologically and genetically distinct from two other causes of inherited renal carcinoma, von Hippel-Lindau disease (VHL) and the chromosome translocation (3;8)(5-6). Malignant papillary renal carcinomas are characterized by trisomy of chromosomes 7, 16 and 17, and in men, by loss of the Y chromosome(7), Inherited and sporadic clear cell renal carcinomas are characterized by inactivation of both copies of the VHL gene by mutation, and/or by hypermethylation(8-11). We found that the HPRC gene was located at chromosome 7q31.1-34 in a 27-centimorgan (cM) interval between D7S496 and D7S1837. We identified missense mutations located in the tyrosine kinase domain of the MET gene in the germline of affected members of HPRC families and in a subset of sporadic Family: papillary renal carcinomas. Three mutations in the MET gene are located in codons that are homologous to those in c-kit and RET, proto-oncogenes that are targets of naturally-occurring mutations. The results suggest that missense mutations located in the MET proto-oncogene lead to constitutive activation of the MET protein and papillary renal carcinomas.